Recombinant Human Advanced glycosylation end product-specific receptor (AGER), partial

Function

Cell surface pattern recognition receptor that senses endogenous stress signals with a broad ligand repertoire including advanced glycation end products, S100 proteins, high-mobility group box 1 protein/HMGB1, amyloid beta/APP oligomers, nucleic acids, histones, phospholipids and glycosaminoglycans (PubMed:27572515, PubMed:28515150, PubMed:34743181, PubMed:35974093, PubMed:24081950). Advanced glycation end products (AGEs) are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes (PubMed:21565706). These ligands accumulate at inflammatory sites during the pathogenesis of various diseases including diabetes, vascular complications, neurodegenerative disorders and cancers, and RAGE transduces their binding into pro-inflammatory responses. Upon ligand binding, uses TIRAP and MYD88 as adapters to transduce the signal ultimately leading to the induction of inflammatory cytokines IL6, IL8 and TNFalpha through activation of NF-kappa-B (PubMed:21829704, PubMed:33436632). Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key pro-inflammatory mediators (PubMed:19386136). Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons (PubMed:19906677). ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Participates in endothelial albumin transcytosis together with HMGB1 through the RAGE/SRC/Caveolin-1 pathway, leading to endothelial hyperpermeability (PubMed:27572515). Mediates the loading of HMGB1 in extracellular vesicles (EVs) that shuttle HMGB1 to hepatocytes by transferrin-mediated endocytosis and subsequently promote hepatocyte pyroptosis by activating the NLRP3 inflammasome (PubMed:34743181). Binds to DNA and promotes extracellular hypomethylated DNA (CpG DNA) uptake by cells via the endosomal route to activate inflammatory responses (PubMed:24081950, PubMed:28515150). Mediates phagocytosis by non-professional phagocytes (NPP) and this is enhanced by binding to ligands including RNA, DNA, HMGB1 and histones (PubMed:35974093). Promotes NPP-mediated phagocytosis of Saccharomyces cerevisiae spores by binding to RNA attached to the spore wall (PubMed:35974093). Also promotes NPP-mediated phagocytosis of apoptotic cells (PubMed:35974093). Following DNA damage, recruited to DNA double-strand break sites where it colocalizes with the MRN repair complex via interaction with double-strand break repair protein MRE11 (By similarity). Enhances the endonuclease activity of MRE11, promoting the end resection of damaged DNA (By similarity). Promotes DNA damage repair in trophoblasts which enhances trophoblast invasion and contributes to placental development and maintenance (PubMed:33918759). Protects cells from DNA replication stress by localizing to damaged replication forks where it stabilizes the MCM2-7 complex and promotes faithful progression of the replication fork (PubMed:36807739). Mediates the production of reactive oxygen species (ROS) in human endothelial cells (PubMed:25401185)

Subcellular Location

Cell membrane (Single-pass type I membrane protein)

Tissue Specificity

Endothelial cells. Increased expression in pre-term labor and preeclampsia placentas compared to controls (PubMed:33918759)

Subunit

Constitutive homodimer; disulfide-linked (PubMed:24081950). Forms homooligomers (PubMed:24081950). Interacts with S100A1 and APP (By similarity). Interacts with S100B, S100A12 and S100A14. Interacts with TIRAP (PubMed:21829704). Interacts with HMGB1 (PubMed:34743181). Interacts with LGP2; this interaction plays an important role in AGER-mediated pro-inflammatory responses and cytokine release (PubMed:33436632). Interacts with double-strand break repair protein MRE11 which is a core component of the MRN complex (PubMed:33918759). The interaction enhances MRE11 endonuclease activity and promotes DNA repair (By similarity). Interacts with the MCM2-7 complex via interaction with complex member MCM2; the interaction is increased following DNA replication stress and stabilizes the MCM2-7 complex at replication forks (PubMed:36807739). Interacts with longistatin, a protein from the saliva of the tick, Haemaphysalis longicornis; the interaction attenuates AGER-mediated production of reactive oxygen species (ROS), activation of NF-kappa-B and expression of adhesion molecules and cytokines in human endothelial cells (PubMed:25401185)

• Neeper M. et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. — J. Biol. Chem. (1992)
• Sugaya K. et al. Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3. — Genomics (1994)
• Abedin M.J. et al. Molecular heterogeneity of the receptor for advanced glycation endproducts. (JAN-)
• Malherbe P. et al. cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products (RAGE) and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein. (MAY-)
• Yonekura H. et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. — Biochem. J. (2003)
• Xie T. et al. Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse. — Genome Res. (2003)
• Hudson B.I. et al. Identification, classification, and expression of RAGE gene splice variants. — FASEB J. (2008)
• Jules J. et al. Alternative splicing of the RAGE cytoplasmic domain regulates cell signaling and function. — PLoS ONE (2013)